Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Large-scale single-neuron speech sound encoding across the depth of human cortex.

Understanding the neural basis of speech perception requires that we study the human brain both at the scale of the fundamental computational unit of neurons and in their organization across the depth of cortex. Here we used high-density Neuropixels arrays1-3 to record from 685 neurons across cortical layers at nine sites in a high-level auditory region that is critical for speech, the superior temporal gyrus4,5, while participants listened to spoken sentences. Single neurons encoded a wide range of speech sound cues, including features of consonants and vowels, relative vocal pitch, onsets, amplitude envelope and sequence statistics. Neurons at each cross-laminar recording exhibited dominant tuning to a primary speech feature while also containing a substantial proportion of neurons that encoded other features contributing to heterogeneous selectivity. Spatially, neurons at similar cortical depths tended to encode similar speech features. Activity across all cortical layers was predictive of high-frequency field potentials (electrocorticography), providing a neuronal origin for macroelectrode recordings from the cortical surface. Together, these results establish single-neuron tuning across the cortical laminae as an important dimension of speech encoding in human superior temporal gyrus.

Neoadjuvant Chemotherapy with Laser Interstitial Thermal Therapy in Central Nervous System Neuroblastoma: Illustrative Case and Literature Review.

Primitive neuroectodermal tumors of the central nervous system, or CNS neuroblastoma, are rare neoplasms in children. Recently, methylation profiling enabled the discovery of four distinct entities of these tumors. The current treatment paradigm involves surgical resection followed by chemotherapy and radiation. However, upfront surgical resection carries high surgical morbidity in this patient population due to their young age, tumor vascularity, and often deep location in the brain. We report a case of CNS neuroblastoma that can be successfully treated with neoadjuvant chemotherapy followed by minimally invasive laser interstitial thermal therapy and radiation. The patient has complete treatment with no evidence of recurrence at one year follow-up. This case illustrates a potential paradigm shift in the treatment of these rare tumors can be treated using minimally invasive surgical approach to achieve a favorable outcome.

DREDge: robust motion correction for high-density extracellular recordings across species.

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

Prevalence of Pediatric Masked Hypertension and Risk of Subclinical Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Masked hypertension (MH) occurs when office blood pressure is normal, but hypertension is confirmed using out-of-office blood pressure measures. Hypertension is a risk factor for subclinical cardiovascular outcomes, including left ventricular hypertrophy, increased left ventricular mass index, carotid intima media thickness, and pulse wave velocity. However, the risk factors for ambulatory blood pressure monitoring defined MH and its association with subclinical cardiovascular outcomes are unclear. A systematic literature search on 9 databases included English publications from 1974 to 2023. Pediatric MH prevalence was stratified by disease comorbidities and compared with the general pediatric population. We also compared the prevalence of left ventricular hypertrophy, and mean differences in left ventricular mass index, carotid intima media thickness, and pulse wave velocity between MH versus normotensive pediatric patients. Of 2199 screened studies, 136 studies (n=28 612; ages 4-25 years) were included. The prevalence of MH in the general pediatric population was 10.4% (95% CI, 8.00-12.80). Compared with the general pediatric population, the risk ratio (RR) of MH was significantly greater in children with coarctation of the aorta (RR, 1.91), solid-organ or stem-cell transplant (RR, 2.34), chronic kidney disease (RR, 2.44), and sickle cell disease (RR, 1.33). MH patients had increased risk of subclinical cardiovascular outcomes compared with normotensive patients, including higher left ventricular mass index (mean difference, 3.86 g/m2.7 [95% CI, 2.51-5.22]), left ventricular hypertrophy (odds ratio, 2.44 [95% CI, 1.50-3.96]), and higher pulse wave velocity (mean difference, 0.30 m/s [95% CI, 0.14-0.45]). The prevalence of MH is significantly elevated among children with various comorbidities. Children with MH have evidence of subclinical cardiovascular outcomes, which increases their risk of long-term cardiovascular disease.

Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases.

OBJECTIVE: Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS: All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS: There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.

A standardized postoperative bowel regimen protocol after spine surgery.

Objectives: Spine surgery is associated with early impairment of gastrointestinal motility, with postoperative ileus rates of 5-12%. A standardized postoperative medication regimen aimed at early restoration of bowel function can reduce morbidity and cost, and its study should be prioritized. Methods: A standardized postoperative bowel medication protocol was implemented for all elective spine surgeries performed by a single neurosurgeon from March 1, 2022 to June 30, 2022 at a metropolitan Veterans Affairs medical center. Daily bowel function was tracked and medications were advanced using the protocol. Clinical, surgical, and length of stay data are reported. Results: Across 20 consecutive surgeries in 19 patients, mean age was 68.9 years [standard deviation (SD) = 10; range 40-84]. Seventy-four percent reported preoperative constipation. Surgeries consisted of 45% fusion and 55% decompression; lumbar retroperitoneal approaches constituted 30% (10% anterior, 20% lateral). Two patients were discharged in good condition prior to bowel movement after meeting institutional discharge criteria; the other 18 cases all had return of bowel function by postoperative day (POD) 3 (mean = 1.8-days, SD = 0.7). There were no inpatient or 30-day complications. Mean discharge occurred 3.3-days post-surgery (SD = 1.5; range 1-6; home 95%, skilled nursing facility 5%). Estimated cumulative cost of the bowel regimen was $17 on POD 3. Conclusions: Careful monitoring of return of bowel function after elective spine surgery is important for preventing ileus, reducing healthcare cost, and ensuring quality. Our standardized postoperative bowel regimen was associated with return of bowel function within 3 days and low costs. These findings can be utilized in quality-of-care pathways.

The Clinical Impact of Recent Methamphetamine Exposure in Aneurysmal Subarachnoid Patients.

Background: Methamphetamines (MA) are a frequently used drug class with potent sympathomimetic properties that can affect cerebral vasculature. Conflicting reports in literature exist about the effect of exposure to MA on vasospasm risk and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to characterize the impact of recent MA use on the timing, severity and features of vasospasm in aneurysmal subarachnoid as well as neurological outcomes. Methods: We retrospectively screened 441 consecutive patients admitted to a tertiary care hospital with a diagnosis of SAH who underwent at least one cerebral digital subtraction angiogram (DSA). Patients were excluded if no urinary toxicology screen was performed within 24 hours of admission, if there was a diagnosis of non-aneurysmal SAH, or if ictus was greater than 72 hours from hospital admission. Vasospasm characteristics were collected from DSA and transcranial doppler (TCD) studies and demographic as well as clinical outcome data was abstracted from the chart. Results: 129 patients were included and 24 tested positive for MA. Among the 312 excluded patients, 281 did not have a urinary toxicology screen and 31 had a non-aneurysmal pattern of SAH or ictus occurring greater than 72 hours from hospital admission. No significant differences were found in respect to patient age, sex, or admission Hunt and Hess Score or Modified Fisher Scale based on MA use. There was no difference in the severity of vasospasm or time to peak severity using either TCD or DSA criteria on multivariate analysis. Aneurysms were more likely to be in the anterior circulation for both groups, however the MA cohort experienced less vasospasm involving the anterior circulation and more isolated posterior circulation vasospasm. There was no difference in delayed cerebral ischemia (DCI) incidence, length of ICU stay, need for ventriculoperitoneal shunt placement, functional outcome at discharge or hospital mortality. Interpretation: Recent MA use was not associated with worse vasospasm severity, time to vasospasm, or DCI in aSAH patients. Further investigations about localized MA effects in the posterior circulation and impact on long-term functional outcomes are warranted.

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.

Validation of a liquid chromatography-tandem mass spectrometry method for simultaneous quantification of N,N-dimethylacetamide and N-monomethylacetamide in pediatric plasma.

N,N-dimethylacetamide is an excipient used in intravenous busulfan formulations, a drug used in hematopoietic stem cell transplantation conditioning. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry method for simultaneous quantification of N,N-dimethylacetamide, and its metabolite N-monomethylacetamide in plasma from children receiving busulfan. A 4 µl aliquot of patient plasma was extracted using 196 µl 50% methanol solution and quantified against calibrators prepared in the extraction solvent given negligible matrix effects across three concentrations. 9 [H2 ]-N,N-dimethylacetamide was used as an internal standard. Separation of N,N-dimethylacetamide and N-monomethylacetamide was achieved using a Kinetex EVO C18 stationary phase (100 mm × 2.1 mm × 2.6 µm) running an isocratic mobile phase of 30% methanol containing 0.1% formic acid at a flow of 0.2 ml/min over 3.0 min. The injection volume was 1 µl. Calibration curves for N,N-dimethylacetamide and N-monomethylacetamide were linear up to 1200 and 200 µg/L, respectively, with a lower limit of quantification 1 µg/L for both analytes. Calibrator accuracy and precision were within ± 10% of the test parameters across four concentration levels. Analytes were stable over 14 days at three different storage conditions. This method was successfully applied to measure N,N-dimethylacetamide and N-monomethylacetamide concentrations in a total of 1265 plasma samples from 77 children.

Risk of Target Organ Damage in Children With Primary Ambulatory Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Target organ damage (TOD) such as left ventricular hypertrophy (LVH), abnormal pulse wave velocity, and elevated carotid intima-media thickness are common among adults with hypertension and are associated with overt cardiovascular events. The risk of TOD among children and adolescents with hypertension confirmed by ambulatory blood pressure monitoring is poorly understood. In this systematic review, we compare the risks of TOD among children and adolescents with ambulatory hypertension to normotensive individuals. METHODS: A literature search was conducted to include all relevant English-language publications from January 1974 to March 2021. Studies were included if patients underwent 24-hour ambulatory blood pressure monitoring and ≥1 TOD was reported. Ambulatory hypertension was defined by society guidelines. Primary outcome was the risk of TOD, including LVH, left ventricular mass index, pulse wave velocity, and carotid intima-media thickness among children with ambulatory hypertension compared with those with ambulatory normotension. Meta-regression calculated the effect of body mass index on TOD. RESULTS: Of 12 252 studies, 38 (n=3609 individuals) were included for analysis. Children with ambulatory hypertension had an increased risk of LVH (odds ratio, 4.69 [95% CI, 2.69-8.19]), elevated left ventricular mass index (pooled difference, 5.13 g/m2.7; [95% CI, 3.78-6.49]), elevated pulse wave velocity (pooled difference, 0.39 m/s [95% CI, 0.20-0.58]), and elevated carotid intima-media thickness (pooled difference, 0.04 mm [95% CI, 0.02-0.05]), compared with normotensive children. Meta-regression showed a significant positive effect of body mass index on left ventricular mass index and carotid intima-media thickness. CONCLUSIONS: Children with ambulatory hypertension have adverse TOD profiles, which may increase their risk for future cardiovascular disease. This review highlights the importance of optimizing blood pressure control and screening for TOD in children with ambulatory hypertension. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020189359.

Dissociation of Broca's area from Broca's aphasia in patients undergoing neurosurgical resections.

OBJECTIVE: Broca's aphasia is a syndrome of impaired fluency with retained comprehension. The authors used an unbiased algorithm to examine which neuroanatomical areas are most likely to result in Broca's aphasia following surgical lesions. METHODS: Patients were prospectively evaluated with standardized language batteries before and after surgery. Broca's area was defined anatomically as the pars opercularis and triangularis of the inferior frontal gyrus. Broca's aphasia was defined by the Western Aphasia Battery language assessment. Resections were outlined from MRI scans to construct 3D volumes of interest. These were aligned using a nonlinear transformation to Montreal Neurological Institute brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm was used to test for areas statistically associated with Broca's aphasia when incorporated into a resection, as well as areas associated with deficits in fluency independent of Western Aphasia Battery classification. Postoperative MRI scans were reviewed in blinded fashion to estimate the percentage resection of Broca's area compared to areas identified using the VLSM algorithm. RESULTS: A total of 289 patients had early language evaluations, of whom 19 had postoperative Broca's aphasia. VLSM analysis revealed an area that was highly correlated (p < 0.001) with Broca's aphasia, spanning ventral sensorimotor cortex and supramarginal gyri, as well as extending into subcortical white matter tracts. Reduced fluency scores were significantly associated with an overlapping region of interest. The fluency score was negatively correlated with fraction of resected precentral, postcentral, and supramarginal components of the VLSM area. CONCLUSIONS: Broca's aphasia does not typically arise from neurosurgical resections in Broca's area. When Broca's aphasia does occur after surgery, it is typically in the early postoperative period, improves by 1 month, and is associated with resections of ventral sensorimotor cortex and supramarginal gyri.

Factors associated with preoperative and postoperative seizures in patients undergoing resection of brain metastases.

OBJECTIVE: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Cortisol and α-amylase awakening response in children and adolescents with functional neurological (conversion) disorder.

OBJECTIVE: Stress system dysregulation is considered to have an important role in the aetiology of paediatric functional neurological (conversion) disorder. This study examined salivary cortisol and α-amylase awakening responses in children with functional neurological disorder to determine activation patterns of the hypothalamic-pituitary-adrenal axis and sympathetic system. A healthy cortisol awakening response involves a robust increase in cortisol within 30 minutes of awakening. Alpha-amylase awakening response is variable in children. METHODS: Cortisol and α-amylase were measured in saliva from 32 patients with functional neurological disorder (26 girls and 6 boys, aged 11.3-16.1 years) and 31 healthy controls (23 girls and 8 boys, aged 8.6-17.7 years). Saliva samples were collected using a Salivette sampling device at two time points - upon awakening and 30 minutes after awakening. RESULTS: Patients with functional neurological disorder showed a decrease in cortisol awakening response (-4 nmol.min/L) and controls showed an increase (107 nmol.min/L), t(55) = -.4.6, p < 0.001. Within the functional neurological disorder group, 57% showed an attenuated cortisol awakening response and 43% showed an obliterated/reversed cortisol awakening response: Cortisol awakening response was negatively correlated with adverse childhood experiences, r(58) = -0.6, p = 0.002, and subjective distress (total Depression Anxiety and Stress Scales score), r(58) = -0.4, p = 0.050. In controls, cortisol awakening response showed no correlation with adverse childhood experiences and a positive correlation with subjective distress, r(56) = 0.4, p = 0.023. Total cortisol remained similar between the functional neurological disorder and control group. No significant differences were observed between the functional neurological disorder and control group in any of the α-amylase analyses. DISCUSSION: The results suggest dysregulation of the hypothalamic-pituitary-adrenal axis in children with functional neurological disorder. Hypothalamic-pituitary-adrenal dysregulation in children with functional neurological disorder may contribute to comorbid symptoms of fatigue, sleep disturbance and subjective loss of well-being because circadian rhythms and energy metabolism are disrupted. Hypothalamic-pituitary-adrenal dysregulation - and changes in glucocorticoid (cortisol) signalling at the molecular level - may also contribute to increased vulnerability for functional neurological disorder symptoms because of epigenetically mediated changes to neural networks implicated in functional neurological disorder.

Childhood nephrotic syndrome and the clinical profile of thromboembolism: a systematic review and meta-analysis.

Nephrotic syndrome (NS) is a common kidney disease of childhood, affecting 2-7 children per 100,000. A potentially life-threatening complication affecting children with NS is thromboembolism (TE). However, there remains a paucity of information regarding the burden of TE and its associated risk factors in this population. A systematic review was performed on observational studies examining TE events in children with NS, published in Medline, Embase, CINAHL, and CENTRAL, until May 2021. Meta-analyses were separately conducted on the prevalence of TE within articles exclusively studying children with congenital NS and among articles including all forms of NS. Out of 13,626 articles, 22 were included (14,290 children). The pooled prevalence of symptomatic TE among articles including patients with all forms of NS was 3.60% (95% CI 1.95-5.63), which increased to 8.70% (95% CI 5.11-12.96) in articles with exclusively congenital NS patients. Children with steroid-resistant NS were at a higher risk of TE compared to steroid-sensitive children (OR 4.40, 95% CI 1.34-15.59, p = 0.013). Focal segmental glomerulosclerosis was the most common histology present in patients with TE (51.2%). Children diagnosed with NS have a significant risk of TE, particularly in patients with congenital NS and steroid resistance. IMPACT: The prevalence of symptomatic thromboembolic (TE) events in children with nephrotic syndrome (NS) was 3.60% (95% CI 1.95-5.63), which increased more than two-fold in children with congenital NS to 8.70% (95% CI 5.11-12.96). Potential risk factors for TE events in this population include congenital forms of NS and steroid resistance. This review provides a better estimate of the prevalence of TE in children with NS, while identifying potentially higher-risk populations who may benefit from TE screening and thromboprophylaxis.

Ultraflexible electrode arrays for months-long high-density electrophysiological mapping of thousands of neurons in rodents.

Penetrating flexible electrode arrays can simultaneously record thousands of individual neurons in the brains of live animals. However, it has been challenging to spatially map and longitudinally monitor the dynamics of large three-dimensional neural networks. Here we show that optimized ultraflexible electrode arrays distributed across multiple cortical regions in head-fixed mice and in freely moving rats allow for months-long stable electrophysiological recording of several thousand neurons at densities of about 1,000 neural units per cubic millimetre. The chronic recordings enhanced decoding accuracy during optogenetic stimulation and enabled the detection of strongly coupled neuron pairs at the million-pair and millisecond scales, and thus the inference of patterns of directional information flow. Longitudinal and volumetric measurements of neural couplings may facilitate the study of large-scale neural circuits.

Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations.

AIM: To investigate the pharmacokinetics (PK) of intravenous treosulfan in paediatric patients undergoing haematopoietic stem cell transplantation (HSCT) for a broad range of diseases and to explore the impact of different dosing regimens on treosulfan exposure (area under the concentration-time curve, AUC0→∞ ) through dosing simulations. METHODS: A prospective multicentre PK study was conducted using treosulfan concentration data (n = 423) collected from 53 children (median age 3.5, range 0.2-17.0 years) receiving three daily age-guided doses (10-14 g/m2 ). Population PK modelling was performed using NONMEM software, utilising a stepwise forward selection backward elimination method and likelihood-ratio test for screening covariates to describe PK variability. Monte Carlo simulation was used to generate patient PK data for 10 000 virtual paediatric patients and cumulative AUC0→∞ values were evaluated using age, body surface area (BSA) and model-based dosing regimens, targeting 4800 mg*h/L. RESULTS: Treosulfan concentration data were described using a one-compartment PK model with first-order elimination. Population mean (95% CI) estimates for clearance (CL) and volume of distribution (V) were 16.3 (14.9-18.1) L/h and 41.9 (38.8-45.1) L, respectively. Allometrically scaled body weight was the best covariate descriptor for CL and V, and maturational age further explained variability in CL. Dosing simulations indicated that in young patient groups (<2 years), a model-based dosing regimen more accurately achieved the target AUC0→∞ (58.3%) over the age (42.6%) and BSA-based (51.3%) regimens. CONCLUSION: Treosulfan disposition was described through allometric body weight and maturational age descriptors. Model-informed dosing is recommended for patients under 2 years. Treosulfan PK parameters and AUC0→∞ were not influenced by patient disease.

Use of an exoscope for enhanced visualization of a Schwab grade 5 osteotomy to correct kyphotic deformity.

The development of the 3D exoscope has advanced intraoperative visualization by providing access to visual corridors that were previously difficult to obtain or maintain with traditional operating microscopes. Favorable ergonomics, maneuverability, and increased potential for instruction provide utility in a large range of procedures. Here, the authors demonstrate the exoscope system in a patient with progressive thoracolumbar junctional kyphosis with bony retropulsion of a T12-L1 fracture requiring a Schwab grade 5 osteotomy and fusion. The utilization of the exoscope provides visual access to the ventrolateral dura for the entire surgical team (surgeons, learners, and scrub nurse). The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21190.

Targeting Accuracy and Clinical Outcomes of Awake versus Asleep Interventional Magnetic Resonance Imaging-Guided Deep Brain Stimulation for Parkinson's Disease: The University of California, San Francisco Experience.

BACKGROUND: Interventional MRI (iMRI)-guided implantation of deep brain stimulator (DBS) leads has been developed to treat patients with Parkinson's disease (PD) without the need for awake testing. OBJECTIVE: Direct comparisons of targeting accuracy and clinical outcomes for awake stereotactic with asleep iMRI-DBS for PD are limited. METHODS: We performed a retrospective review of patients with PD who underwent awake or iMRI-guided DBS surgery targeting the subthalamic nucleus or globus pallidus interna between 2013 and 2019 at our institution. Outcome measures included Unified Parkinson's Disease Rating Scale Part III scores, levodopa equivalent daily dose, radial error between intended and actual lead locations, stimulation parameters, and complications. RESULTS: Of the 218 patients included in the study, the iMRI cohort had smaller radial errors (iMRI: 1.27 ± 0.72 mm, awake: 1.59 ± 0.96 mm, P < .01) and fewer lead passes (iMRI: 1.0 ± 0.16, awake: 1.2 ± 0.41, P < .01). Changes in Unified Parkinson's Disease Rating Scale were similar between modalities, but awake cases had a greater reduction in levodopa equivalent daily dose than iMRI cases ( P < .01), which was attributed to the greater number of awake subthalamic nucleus cases on multivariate analysis. Effective clinical contacts used for stimulation, side effect thresholds, and complication rates were similar between modalities. CONCLUSION: Although iMRI-DBS may result in more accurate lead placement for intended target compared with awake-DBS, clinical outcomes were similar between surgical approaches. Ultimately, patient preference and surgeon experience with a given DBS technique should be the main factors when determining the "best" method for DBS implantation.

Total bilirubin assay differences may cause inconsistent treatment decisions in neonatal hyperbilirubinaemia.

OBJECTIVES: To assess interlaboratory variability of total serum bilirubin (TSB) results in newborns. Initiated following a clinical incident in which a neonate was transferred to a tertiary hospital for treatment of severe hyperbilirubinemia but on arrival was reclassified into a lower risk category due to a 20% difference in TSB between laboratories. METHODS: Fresh residual plasma samples from hospital-born infants were pooled to obtain 11 samples across a range of total bilirubin concentrations. Aliquots were light-protected and measured on 7 commercial platforms at 4 accredited medical laboratories. Data from The Royal College of Pathologists of Australasia Quality Assurance Programs' (RCPAQAP) Neonatal Bilirubin program was analysed. RESULTS: Twenty-four to 30% difference in results for individual samples, largely due to calibration differences between assays. When interpreted according to guidelines, results from different platforms would have led to different clinical interventions in some cases. RCPAQAP results showed significant within-method bias but were not shown to be commutable with patient samples. CONCLUSIONS: There are clinically significant method-dependent differences in TSB results from neonatal samples, consistent with our clinical incident. The differences are largely due to lack of standardisation of calibrator values. This has implications for healthcare resource use and possibly for the neurodevelopment of infants. Intervention is needed at a number of levels, including clinical reporting of incidents arising from discordant results, commitment by manufacturers to ensure metrological traceability of methods with sufficiently low uncertainty in the final measurements, and availability of commutable quality assurance material to monitor assay performance, especially at the clinical decision points for neonatal jaundice.